Derivatives of 1,2,3,4-tetrahydro-5h-benzothieno[2,3-c]azepines

ABSTRACT

The compounds are derivatives of 1,2,3,4-tetrahydro-5Hbenzothieno(2,3-C)azepines useful as antihypertensive and tranquilizing agents. A compound disclosed is 1-ethyl-1,2,3,4tetrahydrobenzothieno(2,3-C)azepine.

United States Patent Sub 1 1 Jan. 30, 1973 [54] DERIVATIVES 0F l,2,3,4-[51] Int. Cl. ..A6lk 27/00, C07d 63/22 TETRAHYDRO-SH-BENZOTHIENOl2,3-[58] Field of Search ..260/330.5 ClAZEPlNES 75 Inventor: John T. Suh,Mequon, Wis. [56] Refe'mes [73] Assignee: Colgate-Palmolive Company, NewUNITED STATES PATENTS Ymk, 3,429,294 1/1970 Suh ..260/240 [22] Filed:Sept. 23, 1970 i Primary Examiner-Hcnry R. .Iiies [21] Appl' 74827Assistant ExaminerCecilia M. S. Jaisle Related Ap-pncafion DataAttorney-T. F. Kryshak and M. L. Youngs [63] Continuation-impart of Ser.No. 876,600, Nov. 13, T

1969, Pat. No. 3,561,068, which is a continuation-in- [57] ABSTRAC partof Ser. No. 705,909, Feb. 16, 1968, Pat. No. The compounds arederivatives of l,2,3,4-tetrahydro- 3,520,895, which iS acontinuatiomin-part of S61. N0. 5H be thieno[2 3 clazepincs useful asantihyper- 621,475 March 1967 abandoned' tensive and tranquilizingagents. A compound disclosed isl-ethyl-l,2,3,4-tetrahydrobenzothieno[2,3- U.S. Cl. ..260/330.5,260/247.1, 260/268 TR, 7

260/293.57, 260/294.8 B, 260/3263, 260/3265 S, 260/3255 A, 260/326.81,260/326.9, 424/248, 424/250, 424/263,

C]azepine.

4 Claims, N0 Drawings DERIVATIVES OF 1,2 ,3 ,4-TETRAHYDRO-5H-BENZOTHIENO[2,3-C ]AZEPINES RELATED CASES The present application is acontinuation-in-part of my copending application Ser. No. 876,600 filedNov. 13, 1969, now US. Pat. No. 3,651,068 which is acontinuation-in-part of my Ser. No. 705,909 filed Feb. 16, 1968, now US.Pat. No. 3,520,895, which is a continuationin-part of my earlierapplication Ser. No. 621,475 filed Mar. 8, 1967, now abandoned.

DETAILED DESCRIPTION The compounds of the present invention have thefollowing formula:

wherein A and A, are selected from hydrogen, hydroxy, nitro, lower alkylgroups of one to four carbon atoms such as methyl, ethyl or isopropyl,lower alkoxy groups such as methoxy, ethoxy and propoxy, halo such asbromo, chloro and fluoro and trifluoromethyl, R is a group selected fromhydrogen, a lower alkyl of one to four carbon atoms, an aralkyl of sevento 11 carbon atoms, such as benzyl, phenethyl and phenylisopropyl, andincluding halo and lower alkoxy substituted phenyl-lower alkyls such aso-chlorobenzyl and p-methoxybenzyl, (CH ),,OH in which n is two to six,and B- Am in which B is an alkylene of two to six carbon atoms and Am isselected from in which R, and R may be the same or different groupsselected from hydrogen, lower alkyl of one to four carbon atoms, loweralkyl-tertiaryamino such as diethylaminoethyl, hydroxy-lower alkyl suchas hydroxyethyl, a lower alkenyl of three to six carbon atoms such asallyl and hexenyl, phenyl, nuclear substituted phenyl, particularly ahalophenyl such as ochlorophenyl and an alkoxyphenyl such asp-methoxyphenyl, cycloalkyl groups, particularly those containing threeto seven carbon atoms and including cyclohexyl and cyclopentyl,cycloalkyl-lower alkyl groups, particularly those in which thecycloalkyl contains three to seven carbon atoms such as cyclohexylmethyland cyclopentyl-ethyl,

b. groups in which represents an amino group such as morpholino,pyrrolidino, piperidino, N-lower alkyl piperazino groups such asN-methyl-piperazino, N-(phenyl-lower alkyl)- piperazino groups such asN-benzylpiperazino and 4- (alpha-methylphenethyl)piper-azino andN-(hydroxy- 6 lower alkyl)-piperazino groups such as4-(beta-hydroxyethyl)-piperazino, and

c. Am is a cyclic amine group bonded through a nuclear carbon to B,including such groups as N-lower alkyl-2,3 or 4-piperidyls such asN-methyl-3-piperidyl, N-ethyl-4-piperidyl, N-ethyI-Z-piperidyl and N-dimethylaminopropyl)-2piperidyl, N-phenyl-lower alkyl-3 or 4-piperidylssuch as N-benzyl-3-piperidyl, N- phenylethyl-4-piperidyl andN-phenylpropyl-3- piperidyl, Z-piperidyl, 3-piperidyl and 4-piperidyl,2- pyrrolidyl, 3-pyrrolidyl, N-lower alkyl-2 or 3-pyrrolidyls such as Nmethyl-Z-Pyrrolidjyl, N-ethyl-B-pyrrolidyl, N-pro'pyl-4-pyrrolidyl, andN-phenyl-lower alkyl-2 or 3-pyrrolidyls such as N-benzyl-Z-pyrrolidyland N phenyl-ethyl-3-pyrrolidyl, X, is hydrogen or lower alkyl and X ishydrogen, a lower alkyl of one to four carbon atoms, phenyl, including anuclear substituted phenyl, particularly a halophenyl such aso-chlorophenyl, or an alkoxyphenyl such as p-methoxyphenyl, aralkyl ofseven to l 1 carbon atoms such as benzyl, phenethyl and phenylisopropyl,and including nuclear substituted aralkyls, particularly halo and loweralkoxy substituted phenyl-lower alkyls, such as o-c hlorobenzyl anddimethoxybenzyl, a heterocyclic such as pyridyl, piperidyl, furyl,thienyl, pyrryl and pyrrolidyl or B-Am.

The basic starting materials employed in the preparation of thecompounds of the present invention are B-(3-thianaph-thenyl)propylamines of the formula Representative of theamines which may be employed are the following:

y-(3-thianaphthenyl)propylamine,

-y-(S-chloro-3-thianaphthenyl)propylamine,

'y-(5-fluoro-3-thianaphthenyl)propylamine,-y-(5-hydroxy-3-thianaphthenyl)propylamine,-y-(6-trifluoromethyl-3-thianaphthenyl)propylamine,y-(5-trifluoromethyl-3-thianaphthenyl)propylamine,'y-(7-methoxy-3-thianaphthenyl)propylamine, and'y-(4-bromo-3-thianaphthenyl)propylamine. The compounds of the presentinvention which are represented by the formula Y GHQ-H1 l I NH s y A1wherein X, is hydrogen may be prepared by treating a'y-(3-thianaphthenyl)propylamine with a suitable aldehyde in aconcentrated liquid organic acid such as glacial acetic acid.

The above described process may be diagrammed as follows:

wherein A and A are as described and do not interfere with or partake inthe reaction.

Representative of the aldehydes which may be employed in the describedprocess are the following:

pyridine-4-carboxaldehyde, V pyridine-2-carboxaldehyde, benzaldehyde,p-methoxybenzaldehyde, dimethylaminobenzaldehyde, Z-furaldehyde,Z-pyrrolecarboxaldehyde, 3-pyrrolecarboxaldehyde,2-thiophenecarboxaldehyde, and 3-thiophenecarboxaldehyde. Representativeof the compounds which may be prepared by the described process are thefollowing:

l-phenyl-l ,2,3,4-tetrahydro-5H-benzothieno[2,3-C

]azepine, l-ethyl-l ,2-,3,4-tetrahydro-5H-benzothienol 2,3-C ]azepine,

l-( p-chlorophenyl )-l ,2,3 ,4-tetrahydro-5 thieno[2,3-C]azepine,l-(ptrifluoromethylphenyl)-l ,2,3 ,4-tetrahydro-5H-benzothieno[2,3-C]azepine, l-(2'-pyridyl)-l ,2,3,4-tetrahydro-5H-benzothieno [2,3 C]azepine, l-(p-methoxyphenyl)-1,2,3,4-

tetrahydrobenzothieno[2,3-C1azepine, l-(2-pyridyl )-7-methoxyl,2,3,4-tetrahydrobenzothieno[2,3-C]azepine,

l -(2'-furyl)-5-bromo-l .2,3,4-tetrahydrobenzothieno [2,3-C1azepine,

l -(m-dimethylaminophenyl)-6-trifluoromethyll,2,3,4-tetrahydrobenzothieno[2,3-C]azepine,

l-( 2-thienyl)-7-methoxy-l ,2,3,4-tetrahydrobenzothieno[2,3-C]azepine,

l 3 ,4'-dihydroxyphenyl )-5-chloro-l,2,3,4-tetrahydrobenzothieno[2,3]azepine,

l-( 3 ,4 ,5'-trimethoxy)-8-fluoro-l ,2,3 ,4-tetrahydrobenzothieno[2,3-C]azepine, and

1-( 3 -furyl)-6-hydroxy-l ,2,3 ,4-

tetrahydrobenzothieno[2,3-C]azepine;

The compounds which are represented by the formu- CHz-CHe I X X2 inwhich X is other than hydrogen may be prepared by a variety of methods.The compounds in which X is methyl may be prepared by treating anappropriate amine with a methyl ketone in the presence of aptoluenesulfonic acid and toluene followed by treatment with an acidsuch as hydrogen chloride in an inert solvent such as ether. Thedescribed process may be illustrated as follows:

A Gin-cm p-toluenesulfonic acid toluene A GHQ-cm l i f The compounds inwhich X is hydrogen and X, is alkyl or aralkyl may also be prepared byfirst treating the corresponding amine with a conventional acylatingagent such as an acyl halide, anhydride or ester, in a suitable solventsuch as benzene, toluene or xylene, preferably at reflux temperature toform the corresponding amide. The resulting amide is then treated withphosphorus pentoxide and phosphorus oxychloride in a suitable anhydrousmedium such as xylene or toluene, to form the ring unsaturated 3,4-dihydrothianaphthieno[ ,3-C1azepine derivative which upon treatment withlithium aluminum hydride yields the desired ring saturated compound.

The above described process may be illustrated as wherein A and A, areas described and represent groups that do not interfere with or partakein the reactions.

Representative of some of the amides prepared by s the process are thefollowing:

N-acetyl-y-( 3-thianaphthenyl )propylamine, N-3-nitropropionyl-y-( 3-thianaphthenyl )propylamine, N-( 3 ,4-dimethoxyphenylacetyl )-'y-(3-thianaphthenyl )propylamine, N-acryloyl-y-( S-thianaphthenyl)propylamine, N-propionyl-y-( 3 -thianaphthenyl )propylam ine,N-(p-methoxyphenylacetyl)-'y-( 3-thianaphthenyl )propylamine,N-iso-butyryl--y-( 3-thianaphthenyl)propylamine, N-butyryl-*y-(3-thianaphthenyl )propylamine,

follows:

GHQ-CH2 acylating CHPCEZ agent NHZ i NH 5 S Al A1 (lllflo POCL; P205 JCHzCHz A CHz-CHz LAH i N I i NH \s y A1 I l X2 i X2 N-[B-(N-methylpiperazinzflfiopionyl] -y-( 3-thianaphthenyl )propylamine,

N-methyl-N-l B-(diethylamino )propionyl ]-'y-( 5-chloro-3-thianaphthenyl )propylamine,

N-dimethylamino acetyl-y- 5 -fluoro-3 -thianaphthenyl)propylamine,

N-y-( diethylamino )butyryl-y-( S -hydroxy-3-thianaph-thenyl)propylamine, and

N-B-(N'-hydroxyethylpiperazino)propionyl-y-(S-tril-(fi-diethylaminoethyl)-6-hydroxy-3,4-dihydro-5H- I benzothieno[2,3-C]azepine,

l-methyl-3 ,4-dihydro-SH-benzothieno 2,3-C

]azepine,

l-(3',4'-dimethoxyphenyl)-3,4-dihydro-5l-l-benzothie n0[2,3-C]az'epine,

6-chlorol -ethyl-3 ,4-dihydro-5 H-benzothieno [2,3

Clazepine,

l-[ 4'-(N-methylpiperidyl ]-7-trifluoromethyl-3 ,4-

dihydro-5l-l-benzothieno[2,3-C]azepine,

l-iso-propyl-l ,2,3 ,4-tetrahydro-5H- benzothieno[2,3-C]azepine.

l-ethyl-l ,2,3,4-tetrahydro-5l-l-benzothieno[2,3-C

lazepine,

l -propyl-1 ,2,3 ,4-tetrahydro-5H-benzothieno[ 2,3-C

]azepine,

l -methyl-1 ,2,3,4-tetrahydro-SH-benzothieno[2,3-C

lazepine,

l-( 3 ,4-dimethoxyphenyl)-l ,2,3 ,4-tetrahydro-5H-benzothieno[2,3-C1azepine,

7-chlorol -ethyl-l ,2,3 ,4-tetrahydro-5l-lbenzothieno[2,3-C1azepine,

l-[4-(N-methylpiperidyl)]-7-trifluoromethyll,2,3,4-tetrahydrobenzothieno[2,3-C]azepine,

l-[ fl-(N-hydroxyethylpiperazino )ethyl] .-7-methoxy-1,2,3,4-tetrahydrobenzothieno[2,3-C]azepine, and

7-hydroxyl -(N-methylpiperazinoethyl)-l ,2,3 ,4-

tetrahydrobenzothieno[ ,3-C ]azepine.

The compounds of the present invention in which R, X and X, are hydrogenmay be prepared by several methods. For example, they may be prepared bytreating a corresponding amine with parafonnaldehyde in an acetatebuffer such as sodium acetate and acetic acid or reduction of thecorresponding lactam.

The two processes may be diagrammed as follows:

GHz-CH:

Cm-CHT Representative of the compounds which may be prepared are thefollowing: 7, V A

' l,2,3,4-tetrahydro-5H-beniothieno[i,3-C]azepine, 6-chloro-l,2,3,4-tetrahydro-5 H-benzothieno[2,3-C

jazepine,

7-chloro-l ,2,3,4-tetrahydro-5H-benzothieno[2,3-C

]azepine, I 8 -chloro-l,2,3,4-tetrahydro-5H-benZothienol2,3-C

]azepine, 9-chloro-l ,2,3,4-tetrahydro-5H-benzothienol2,3-C

]azepine,

6-f1uoro-l ,2,3 ,4-tetrahydro-5H-benzothieno[ 2,3-C

lazepine,

7-fluoro-l ,2,3 ,4-tetral1ydro-SH-benzothienol 2,3-C

]azepine,

8-fluoro-l ,2,3 ,4-tetrahydro-5H-benzothieno[ 2,3-C

lazepine,

9-fluoro-l ,2,3,4-tetrahydro-5H-benzothieno[2,3-C

]azepine,

benzothieno[2,3-C]azepine,

7-trifluoromethyl-l ,2,3 ,4-tetrahydro-5H- benzothieno[2,3-C1azepine,

8-trifluoromethyl-l ,2,3,4-tetrahydro-SH- benzothien0[2,3-C]azepine,

9-trifluoromethyll ,2 ,3 ,4-tetrahydro-5H- benzothieno[2,3-C]azepine,

7-bromo-l ,2,3,4-tetrahydro-5H-benzothieno[ 2,3-C

lazepine,

8-bromo-l ,2,3,4-tetrahydro-5H-benzothieno[ 2,3-C

]azepine, 7-hydroxyl ,2,3 ,4-tetrahydro-5H-benzothienolZ,3-

Clazepine, 8-hydroxy-l ,2,3,4-tetrahydro-SH-benzothienol2,3-

Clazepine,

7,8 -dihydroxy-l ,2,3 ,4-tetrahydro-5H- benz otheino[2,3-Cjazepine,

7-methoxy-l ,2,3 ,4-tetrahydro-SH-benzothieno[ 2,3-

C]azepine, 8-methoxyl ,2,3 ,4-tetrahydro-5H-benzothienol 2,3-

C]azepine, and

7,8-dimethoxy-l ,2,3,4-t trahydro-SH- benzothieno[2,3 -C]azepine.

The compounds of the present invention in which R is lower alkyl may beprepared from the compounds in which R is hydrogen by a variety ofconventional alkylation procedures. For example, the alkyl derivativesmay be prepared by treating the unsubstituted compound with an alkylhalide or by treating it with an acyl halide, followed by reduction ofthe acyl derivative with an alkali metal hydride such as lithiumaluminum hydride. The compounds in which R is methyl are mostconveniently prepared by treating the unsubstituted compound withformaldehyde and formic acid.

CHrCHs GHQ-CH2 I HCHO I NH HCOOH N s X1 X: A X1 X3 1 X Y R x GIL-CH1 AoH -om i LAH W N-d-R was-(mp1s s X Xi 2 wherein RX is an alkylatingagent such a s aii alkyl halide or a reactive ester and is an acylhalide.

Representative of the compounds which may be prepared by the describedprocesses are the following: l-ethyl-2methyl-6-methoxy-l,2,3,4-tetrahydro-5H benzothieno[2,3-C]azepine,1-methyl-2-benzyl-7-chloro-l ,2,3,4-tetrahydro-5H- in which R is B-Amare conveniently prepared by first treating a correspondingunsubstituted compound with an aminoacyl halide to form thecorresponding acyl amine derivative and then treatingit with a chemicalreducing agent such as LAH or other metal hydrides to form the aminederivative.

The described process may be illustrated as follows:

i if

Am-B-C-halo Wherein X X A and A are as described and do not interferewith or partake in the reaction.

Representative of the aminoacylhalides which may be used in the abovedescribed process are the followmg: I

3-(diethylamino)propionyl halide, 2-(dimethylamino)acetyl halide,3-(N-benzyl-N-methylamino)propionyl bromide, 2-(N,N-dibenzylamino)acetylhalide, 3-( N-phenyl-N-methylamino )propionyl bromide,'y-(N-methylpiperazino)butyryl chloride, B-(N-methylpiperazino)propionyl chloride, B-(morpholino)propionyl chloride,B-[3-( N -methyl)pyrrolidyl]propionyl chloride, and'y-(piperidyl)butyryl chloride.

Representative of the compounds which may be prepared in the describedmanner are the following:

Z-B-diethylaminopropionyll -phenyl-l ,2,3,4-tetrahydro-5H-benzothieno[2,3-C]azepine, 2-B-diethylaminopropionyll-methyl-l ,2,3,4-tetrahydro-5l-l-benzothieno[2,3-C]azepine,

Z-B-dimethylaminoacetyll -phenyl-l ,2,3,4-

tetrahydro-SH-benzothieno[2,3-Clazepine,

Z-B-dimethylaminoacetyl- 1 -methyl-] ,2,3,4-

tetrahydro-5H-benzothieno[2,3-C]azepine, 40

1-ethyl-2-fl-diethylaminopropionyl-6-chloro-l ,2,3,4-

tetrahydro-5H-benzothieno[2,3-C]azepine,

Iy-dimethylaminopropyl-2-acetyl-7-methoxyl,2,3,4-tetrahydro-5H-benzothieno[2,3-C ]azepine,

2-y-diethylaminopropyl-l -phenyll ,2,3 ,4-

tetrahydro-SH-benzothieno[2,3-C]azepine,

Z-B-diethylaminopropyl-l-methyl-1,2,3,4-

tetrahydro-SH-benzothieno[2,3-C]azepine,

Z-B-dimethylaminoethyl- 1 -phenyl-l ,2,3,4-

tetrahydro-SH-benzothieno[2,3-C]azepine,

Z-B-dimethylaminoethyl-l-methyl-1,2,3,4-

tetrahydro-SH-benzothieno[ 2,3-C ]azepine,

2-'y-diethylaminopropyl-7-chloro-l ,2,3,4-

tetrahydro-SH-benzothieno[ 2,3-C ]azepine, and

2-y-dimethylaminopropyl-7-trifluoromethyl-l ,2,3,4-

tetrahydro-SH-benzothieno[2,3-C]azepine.

The compounds in which R is BAm may also be prepared by first treatingthe corresponding unsubstituted compound with an 01,62 unsaturated acylha- 50 lide, such as acrylic halide, followed by treatment with an amineand lithium aluminum hydride.

The described process may be illustrated as follows:

wherein X X A and A, are as described and do not partake in or interferewith the reaction.

The above described process provides a convenient means of preparingthose compounds which might not be conveniently prepared by the use ofaminoacylhalides because of their commercial unavailability.

Representative of the compounds which might be conveniently prepared bythe described method are the following:

A variety of compounds in which R is other than amino may also beprepared by use of conventional techniques. For example, the compoundsin which R is hydroxyethyl may be prepared by treating the correspondingl-substituted compound with ethylene oxide. The described reactions maybe illustrated as follows:

in which X X,, A and A, are as described and do not partake in orinterfere with the reactions.

The novel compounds of the present invention may be used asintermediates in the preparation of more complex chemical andpharmaceutical compounds, and because of their antiserotonin activityare valuable pharmacological tools. In addition, they are useful aspharmaceutical agents, per se, because of their antipsychoticproperties, especially their ability to control antisocial aggressivebehavior when administered to anima1s.'For example, the compound1-phenyl-1,2,3,4- tetrahydrobenzothieno[2,3-C]azepine hydrochloride hasshown at a safe and effective dose of approximately 20 mg/kgintraperi-toneally an ability to decrease or inhibit the antisocialbehavioral characteristics such as aggressiveness, viciousness andpersistence for fighting, induced by isolation in mice. The compound wasalso found to have LD s in mice in excess of 75 mg/kg intraperitoneallyin behavioral studies conducted in accordance with procedures outlinedby Irwin in Animal and Clinical Pharmacologic Techniques in DrugEvaluation, .1. H. Nodine and P. E. Siegler, Ed., Year Book Publishers,Inc., 1964, pp. 36-54.

' The following compounds were found to lower blood pressure whenadministered in and 10.0 mg/kg intravenous doses to the vagotomized,anesthesized cat preparation, which is a standard animal preparation fortesting for antihypertensive activity:

1 -pheny1-l ,2,3 ,4-tetrahydrobenzothienol 2,3-

claze pine hydrochloride, and

1 -ethyl-1 ,2,3,4-tetrahydrobenzothieno[ 2,3-

C]azepine hydrochloride.

The novel compounds in which R is B-Amare also useful as they form saltswith penicillins which can be used to aid in the isolation andpurification of the antibiotics.

Acid addition salts of the compounds of the present invention may beconveniently prepared by contacting the compounds which are capable offorming such salts with a suitable acid such as formic acid, citricacid, maleic acid, sulfuric acid, hydrochloric acid, succin'ic acid,tartaric acid, benzoic acid or fumaric acid.

Quaternary ammonium salts may be formed by cont-acting the salt formingcompounds with a suitable alkylating agent such as dimethyl sulfate oran alkyl halide such as methyl chloride, methyl iodide or ethyl bromide-When intended for use as pharmaceuticals, the compounds are preferablycombined with a major amount of one or moresuitable pharmaceuticaldiluents and formed into unit dosage forms. Such dosage forms providesuitable means for oral and parenteral administration.

The pharmaceutical diluents which may be employed may be either liquidor solid, but the preferred liquid carrier iswater. 1n the event thecompound is not soluble in water a pharmaceutically acceptable organicsolvent such as propylene glycol may beemployed.

Solid pharmaceutical diluents such as starch, sugar and talc canbeutilized to form powders which can in turn be used as such or may betableted or encapsulated. In addition to the forementioned material, awide variety of conventional pharmaceutical lubricants, disintegratingagents, flavoring agents and the like, may also be employed.

The unit dosage forms may contain a concentration of 0.1 to 10 percentor more by weight of one or more of the novel compounds. Generally, suchdosage forms will contain about 5 to 250 mg. of the active ingredients.One or more of such dosage forms may be administered daily. The usualintravenous dose will be equivalent to approximately 10 mg/kg of thepatients body weight.

The following examples arepresented to illustrate this invention:

EXAMPLE 1 B-( 3 -Thian aphthenyl )propionamide A mixture of 30 g. (0.145mole) of 3-thianaphthenepropionic acid and 50 ml. (0.7 mole) of SOCl, isheated at 50-67. for 1.5 hours and allowed to cool to 30 in 1.5 hours.It is concentrated in vacuo and theresidue dissolved in 50 m1. of ether.It is added dropwise to ml. of NH,OH solution at 5 in 0.5 hours. Themixture is heated until all ether has been removed, cooled and thesolids collected and dried to yield B-(3-thianaphthenyl)propionamide asa white solid; m.p. 98l00bL.

Anal. Calcd. for CHHHNSOLC, 64.37; H, 5.40; N,

Found: C, 64.87; H, 5.45; N, 6.84.

EXAMPLE 2 'y-(3-Thianaphthenyl)propylamine Hydrochloride To a dispersionof 13.4 g. (0.354 mole) of LiAlH, in i 200 ml. of ether is added adispersion of 24.2 g. (0.118 mole) of 3-thianaphthenepropionamide in 800ml. of ether in 0.5 hours. The mixture is refluxed for 16 hours afterwhich 200 ml. of benzene is added and refluxed again for 1.5 hours. Thecomplex is decomposed with 60 m1. of water and the solid removed byfiltration. The filtrate is dried (Na SO,), and concentrated to yield atheoretical amount of an oil. A 3.0 g. portion of this material isdissolved in ether and acidified with ethereal HCl. The solids arecollected and recrystallized twice from 2-propional to yield-y-(3-thianaphthenyl)propylamine hydrochloride as white crystals, m.p.l87-l 89.

Anal. Calcd.-for C H CINS: C, 58.00; H, 6.20;'N,

6.16. Found: C, 58.27; H, 6.30; N, 6.16.

7 EXAMPLE 3 N-Propionyl-y-( 3-thianaphthenyl)propylamine To a solutionof 9.1 g. (0.098 mole) of propionyl chloride in ml. of benzene is addeda solution of] 5 g. (0.0784 mole) of y-(3-thianaphthenyl)propylamine and7.75g. (0.098 mole) of pyridine in 0.5 hours at 10. The mixture isstirred at 10 for 1 hour, at 25 for 17.5 hours, and refluxed for 1.5hours. The mixture is cooled and 100 ml. of water added and stirred 5minutes. The organic layer is separated and washed successively with 100ml. 10 percent HCl solution'and 50 ml. of brine. It is dried (Na SO,)and concentrated to yield the theoretical amount ofa yellow oil. A 5.0g. portion is chromatographed through alumina using varying proportionsof benzene/petroleum ether and ether/benzene to yield an oil whichcrystallizes on standing to yield a light yellow solid, m.p. 55-57.5.

Anal. Calcd. for C,.,H,,NSO: C, 67.97; H, 6.92; N,

5.66;S, 12.95. Found: C, 68.21; H, 6.92; N, 5.535; S, 13.08.

EXAMPLE 4 1-Ethyl-3 ,4-dihydro-5H-benzothieno[2,3-C]azepine F umarateEthanolate A mixture of 10 g. (0.0404 mole) of N-(propionyl)-3-(fl-aminopropyl)thianaphthene, 16.4 g. (1.15 moles) of P 0 and 16.4 g.(1.06 moles) of POCl in 250 ml. of xylene is refluxed for 2 hours. Themixture is cooled and 400 ml. of water added. The mixture is basifiedwith NaOH flakes after which 200 ml. of CHCl is added and stirred 15minutes. The organic layer is separated, washed with brine, dried (NaSO,) and concentrated to yield a brown oil which is chromatographedthrough alumina using benzene as the eluent to 25 yield a yellow oilwhich crystallizes upon standing.

A portion of this material (2.5 g., 0.01 1 mole) is dissolved in ml. ofethanol and added to a solution of 1.4 g. (0.012 mole) of fumaric acidin ml. of ethanol, filtered and cooled. The solids are collected anddried to yield 1-ethyl-3,4-dihydro-5H- benzothieno[2,3-C]azepinefumarate ethanolate as a yellow solid, m.p. l58160.

Anal. Calcd. for C ,,H NSO C, 61.40; H, 6.40; N,

3.58; S, 8.19. Found: C, 61.45; H, 6.72; N, 3.60; S, 8.15.

EXAMPLE 5 l-Ethyl-1,2,3 ,4-tetrahydro-5 H-benzothieno[2,3-C

]azepine Hydrochloride To a dispersion of 2.4 g. (0.63 mole) of LiAlH in100 ml. of tetrahydrofuran is added a solution of 3.6 g. (0.016 mole) ofl-ethyl-3,4-dihydro-5H- benzothieno[2,3-C]azepine in 100 ml. oftetrahydrofuran in 10 minutes after which it is refluxed for 8 hours.

The complex is decomposed with 15 ml. of water and filtered. Thefiltrate is dried and concentrated to yield an oil which waschromatographed through A1 0,, using ether as an eluent to yield acrystalline solid which is dissolved in ether and acidified withethereal HCl. The solids are collected and refluxed in 60 ml. of

acetonitrile and cooled. The solids are collected and dried to yieldl-ethyl-l ,2,3,4-tetrahydro-5H- benzothieno[2,3-C]azepine hydrochlorideas a white powder, m.p. 238-240.

Anal. Calcd. for C,,H,,,C1NS: C, 62.78; H, 6.78; N,

5.24. Found: C, 62.97; H, 7.05; N, 5.04.

EXAMPLE 6 1-Phenyl-3,4-dihydro-5H-benzothieno[ 2,3-C ]azepine To amixture of 24.8 g. (0.174 mole) of P 0 and 24.8 g. (0.161 mole) of POCl,in 300 ml. of dry xylene is added 18.16 g. (0.0015 mole) ofN-benzoyl-y-(3- thionaphthenyl)propylamine after which the mixture isrefluxed for 2 hrs. Water (700 ml.) is then added and the mixture heatedon a steam bath for 0.5 hrs. The organic layer is separated andextracted with 200 ml. of water. The combined aqueous solution iscooled, filtered, and basified with pellet NaOH. It is extracted threetimes with ml. portions of benzene. The combi'ned extracts are washedwith water, dried and concentrated to yield a clear oil which waschromatographed through alumina g.) using varying proportions of CHCland benzene to yield 1-phenyl-3,4-

dihydro-SH-benzothieno[2,3-C]azepine as a clear viscous oil.

Anal. Calcd. for C,,,H, NS: C, 77.94; H, 5.45; N,

v 5.05;s, 11.55. Found: C,77.65; 11, 5.59; N, 5.32; s, 11.41.

EXAMPLE 7 To a dispersion of 2.2 g. (0.0575 mole) of LiAlH, in 100 ml.of ether is added a solution of 4.0 g. (0.0144 mole) ofl-phenyl-3,4-dihydro-5H-benzothieno[2,3-C] azepine in 50 ml. of ether in0.2 hrs. after which it is refluxed for 18 hrs. The complex isdecomposed with 9 ml. of water and the solids removed by filtration. Thefiltrate is dried and acidified with ethereal/HCI. The solids arecollected and recrystallized from ethanol/ether and again fromacetonitrile/Z-propanol to yield 7 l-phenyl-l ,2,3 ,4-tetrahydro-5H-benzothieno[2,3-C]azepine hydrochloride as a white light textured solidin two crops, m.p. 239242.

Anal. Calcd. for C, H,,,ClNS: S, 10.l6.

Found: S, 10.24.

We claim:

l. A compound selected from compounds and pharmaceutically acceptablesalts of compounds of the formula wherein A and A, are selected fromhydrogen, hydroxy, nitro, lower alkyl, lower alkoxy, halo andtrifluoromethyl, R is selected from hydrogen and (CH nOH in which n istwo to six, X, is hydrogen or lower alkyl and X is selected fromhydrogen, lower alkyl, phenyl, phenyl substituted by halo or loweralkoxy, phenyl-lower alkyl, and phenyl-lower alkyl wherein the phenylgroup is substituted by halo or lower alkoxy.

2. A compound of claim 1 in which A, A,, R, X, and X 'are hydrogen.

3. A compound of claim 1 in which A, A,, X and R are hydrogen and X isethyl.

4. A compound of claim 1 in which A, A,, X, and R are hydrogen and X isphenyl.

1. A compound selected from compounds and pharmaceutically acceptablesalts of compounds of the formula
 2. A compound of claim 1 in which A,A1, R, X1 and X2 are hydrogen.
 3. A compound of claim 1 in which A, A1,X1 and R are hydrogen and X2 is ethyl.